title: A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation.
abstract: OBJECTIVE
  This study describes a novel heterozygous gain-of-function mutation in the cardiac sodium (Na+) channel gene, SCN5A, identified in a Japanese family with lone atrial fibrillation (AF).
  
  
  BACKGROUND
  SCN5A mutations have been associated with a variety of inherited arrhythmias, but the gain-of-function type modulation in SCN5A is associated with only 1 phenotype, long-QT syndrome type 3 (LQTS3).
  
  
  METHODS
  We studied a Japanese family with autosomal dominant hereditary AF, multiple members of which showed an onset of AF or frequent premature atrial contractions at a young age.
  
  
  RESULTS
  The 31-year-old proband received radiofrequency catheter ablation, during which time numerous ectopic firings and increased excitability throughout the right atrium were documented. Mutational analysis identified a novel missense mutation, M1875T, in SCN5A. Further investigations revealed the familial aggregation of this mutation in all of the affected individuals. Functional assays of the M1875T Na(+) channels using a whole-cell patch-clamp demonstrated a distinct gain-of-function type modulation; a pronounced depolarized shift (+16.4 mV) in V(1/2) of the voltage dependence of steady-state inactivation; and no persistent Na+ current, which is a defining mechanism of LQTS3. These biophysical features of the mutant channels are potentially associated with increased atrial excitability and normal QT interval in all of the affected individuals.
  
  
  CONCLUSIONS
  We identified a novel SCN5A mutation associated with familial AF. The mutant channels displayed a gain-of-function type modulation of cardiac Na+ channels, which is a novel mechanism predisposing to increased atrial excitability and familial AF. This is a new phenotype resulting from the SCN5A gain-of-function mutations and is distinct from LQTS3.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.forename: Masaharu
authors.initials: M
authors.lastname: Akao
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shizuta
authors.forename: Takahiro
authors.initials: T
authors.lastname: Doi
authors.forename: Kei
authors.initials: K
authors.lastname: Nishiyama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Oka
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nishio
authors.forename: Keiko
authors.initials: K
authors.lastname: Tsuji
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000235:genetics* / Q000601:surgery; D017115:Catheter Ablation / Q000379:methods; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D007564:Japan; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels